Efficient single-strand cleavage of DNA mediated by a Mn^IIIMn^IV-based artificial nuclease

Abstract

A water-soluble Mn(IV) 1,4,7-triazacyclononane complex, [Mn(IV)2L2(μ-O)2](ClO4)2·2H2O (1), was prepared to serve as a nuclease mimic (L = 1,4,7-triazacyclononane-N-acetate). Complex 1 was readily synthesized from the highly water soluble ligand (L), with Mn(III) salt, [Mn3O(MeCO2)7]·3H2O in basic condition, and characterized by X-ray, IR, electronic spectroscopy, cyclic voltammetry and magnetic susceptibility as well as ESI-MS. The bond valence sum (BVS) analysis and magnetic data suggest that 1 is a Mn(IV)-μ-O2-Mn(IV) species. The electrospray mass spectrum and electronic spectrum of 1 in aqueous solution indicates that dinuclear Mn complex [Mn(III)Mn(IV)L2(μ-O)2](+) (2) is the active species. A predominantly hydrolytic cleavage mechanism was confirmed through experiments performed in the presence of various radical scavengers, T4 ligase and under anaerobic conditions. The kinetic aspects of DNA cleavage under pseudo- or true-Michaelis-Menten conditions were also detailed, kinetic parameters (kcat, KM, Vmax) were calculated to be 6.27 h(-1), 7.35 × 10(-5) M, 4.6 × 10(-4) M h(-1); 0.683 h(-1), 1.93 × 10(-5) M, 1.32 × 10(-5) M h(-1) for 2, respectively.

Transition metal complexes as self-activating chemical nucleases: proficient DNA cleavage without any exogenous redox agents

“…Distinctively from the more familiar and systematic development of mononuclear complexes, multinuclear complexes have been far less investigated, with exiguous examples reported so far. 34,35 Nevertheless, multinuclear complexes may offer unique characteristics and features as a result of their relatively higher DNA binding compared to their mononuclear analogues. For instance, the electron-deficient nature of increasing number of metal ions remarkably enhances the electrostatic attraction between resultant multinuclear species and negatively charged DNA.…”

“…Indeed, some multinuclear complexes have enabled remarkable breakthroughs as potential diagnostic and therapeutic agents. [34][35][36] Although the higher DNA binding of multinuclear complexes may not directly be linked to increased DNA cleavage activity, factors such as the fine-tuning and the flexibility of the ligand frame, as well as the metal-metal distances play an important role in promoting the scission of a specific DNA strand. The concomitance of different electropositive cations in multinuc-lear complexes typically provides the supplemental flexibility to finely tailor the structural parameters, notably distances, geometries, and nature of the linkers between the metal centres, and implicitly better control the related DNA binding features.…”

Dinuclear Cu(II) complexes based on p‐xylylene‐bridged bis(1,4,7‐triazacyclononane) ligands: Synthesis, characterization, DNA cleavage abilities and evaluation of superoxide dismutase‐ and catalase‐like activities

“…Recently, numerous and diverse redox‐active transition metal complexes based on N‐donor ligands have been reported to exhibit marked catalytic effect on the disproportionation of reactive O 2 •− or H 2 O 2 in vitro and some pentaazamacrocyclic Mn(II) compounds as antioxidant SOD mimics have found biomedical applications in preclinical or clinical trials . As a facially coordinated tridentate macrocycle, 1,4,7‐triazacyclononane (tacn) and its derivatives are apt to construct thermodynamically stable and kinetically inert metal complexes, and some of these compounds have manifested an ability to cleave DNA or protein . In the past two decades, several Cu(II) or Mn(II) complexes containing N‐functionalized mono‐tacn ligands with unsaturated or labile binding sites have been reported to show a considerable antioxidant effect on the scavenging of superoxide radical in the physiological environment .…”